Method of preparing inhibitors of phosphodiesterase-4

Abstract

In one aspect, the present invention is directed to a one pot method of preparing intermediates of Formula V, which are useful in making inhibitors of phosphodiesterase-4: The present invention is also directed to a method of preparing phosphodiesterase inhibitors comprising the Formula

1. A method of preparing a compound of Formula LX 
                 
 
       Or a pharmaceutically acceptable salt thereof, comprising
 Step C: reacting, in solvent A, a compound of Formula Va 
                 
 
 
       wherein
 —OR 1  is a suitable leaving group; and  
 solvent A is selected from the group consisting of dimethylacetamide, dimethylformamide, acetonitrile, DMSO, methylacetamide, ethers or mixtures thereof; with a compound of Formula VII 
                 
 
  or free base thereof, in the presence of a palladium catalyst and a phosphine ligand and a second base to yield a compound of Formula VIII 
                 
 
 Step D: reacting, in water a compound of Formula VIII with sodium or potassium hydroxide to yield a compound of Formula VIIIa 
                 
 
  and  
 Step E: reacting, in solvent B, a compound of Formula VIIIa with cyclopropylamine in the presence of an activating agent to yield a compound of Formula IX 
                 
 
 
       wherein solvent B is selected from the group consisting of dimethylaminoacetamide, dimethylformamide, acetonitrile, DMSO, methylacetamide, dichloromethane, ethers or mixtures thereof. 
     
     
       2. A method according to  claim 1  wherein the compound of formula Va is 
                 
 
       and the compound of Formula VIII is 
                 
 
     
     
       3. A method according to  claim 1  wherein the second salt is a carbonate base. 
     
     
       4. A method according to  claim 1  wherein the phosphine ligand is selected from the group consisting of P(C 1-6 alkyl) 3 , such as P(t-butyl) 3 , P(Cy) 3 , and P(t-butyl) 2 (biphenyl). 
     
     
       5. A method according to  claim 1  wherein the palladium catalyst is selected from the group consisting of P(t-butyl) 3 -Pd—P(t-butyl) 3 ), [PdCl(allyl)] 2 , Pd 2  (dba) 3 , and [P(t-butyl) 3 PdBr] 2  (Johnson-Matthey catalyst). 
     
     
       6. A method according to  claim 1  wherein the second base is selected from sodium or potassium carbonate and sodium or potassium phosphate. 
     
     
       7. A method according to  claim 1  wherein the activating agent is selected from carbonyl diimidazole and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. 
     
     
       8. A method according to  claim 1  wherein the compound of formula Va is 
                 
 
       and the compound of Formula VIII is 
                 
 
       the second salt is a carbonate base, 
       the phosphine ligand is selected from the group consisting of P(C 1-6 alkyl) 3 , such as P(t-butyl) 3 , P(Cy) 3 , and P(t-butyl) 2 (biphenyl), 
       the palladium catalyst is selected from the group consisting of P(t-butyl) 3 -Pd—P(t-butyl) 3 ), [PdCl(allyl)] 2 , Pd 2  (dba) 3 , and [P(t-butyl) 3 PdBr] 2  (Johnson-Matthey catalyst), 
       the second base is selected from sodium or potassium carbonate and sodium or potassium phosphate, and 
       the activating agent is selected from carbonyl diimidazole and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. 
     
     
       9. A method of preparing a compound of Formula IX 
                 
 
       Comprising
 Step E: reacting, in solvent B, a compound of Formula VIIIa 
                 
 
  with cyclopropylamine in the presence of an activating agent to yield a compound of Formula IX 
                 
 
 
       wherein solvent B is selected from the group consisting of dimethylaminoacetamide, dimethylformamide, acetonitrile, DMSO, methylacetamide, dichloromethane, ethers or mixtures thereof. 
     
     
       10. A method according to  claim 9  wherein the activating agent is selected from carbonyl diimidazole and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. 
     
     
       11. A method according to  claim 9  further comprising
 Step D: reacting, in water a compound of Formula VIII 
                 
 
  with sodium or potassium hydroxide to yield a compound of Formula VIIIa. 
                 
 
 
     
     
       12. A method according to  claim 11  wherein the activating agent is selected from carbonyl diimidazole and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. 
     
     
       13. A method according to  claim 11  wherein reaction step D and reaction Step E are carried out without purification or isolation of the product of Step D prior to proceeding with Step E.